The strategic breakdown: CHAC enzymes as regulators of glutathione homeostasis and disease implications.

ABSTRACT: This review explores the critical function of the evolutionarily conserved ChaC-like enzyme family as central regulators of intracellular glutathione (GSH) homeostasis, focusing on the mammalian isoforms CHAC1 and CHAC2. We detail how these γ-glutamylcyclotransferases degrade GSH, thereby modulating cellular redox balance and integrating diverse stress signaling pathways. CHAC1 emerges as a key stress-responsive effector, transcriptionally upregulated via the ATF4-CHOP axis during endoplasmic reticulum stress and amino acid deprivation. Its role is especially crucial in the induction of ferroptosis, an iron-dependent cell death pathway, positioning it as a context-dependent modulator of cancer progression, neurotoxicity and neurodegeneration. Furthermore, we examine the opposing rol

SUBMITTER: Schroder E 

PROVIDER: S-EPMC12756093 | biostudies-literature | 2025

REPOSITORIES: biostudies-literature